PT800527E - NEW PROCESSES FOR THE PREPARATION OF INTERMEDIARIES OF ENCEPHALINASE INHIBITORS AND ANGIOTENSIN CONVERSION ENZYME AND ITS INTERMEDIARIES - Google Patents

Description

I

The present invention relates to novel processes for the preparation of compounds of general formula I. The invention relates to novel processes for the preparation of compounds of general formula I. The invention relates to novel processes for the preparation of compounds of general formula I.

which are useful intermediates for the preparation of enkephalinase inhibitors and angiotensin converting enzyme, including [4S- [4Î ±, 7a (R *), 12β]] - 7 - [(1-oxo-2 (S) -thio-3-phenylpropyl) amino] -1,2,3,4,6,7,8,12b-octa 6-oxo-pyrido [2,1-a] [2] benzazepine-4-carboxylic acid and [4S- [4Î ±, 7Î ± (R *), 12β]] - 7 - [(1-oxo-2- (S) -acetylthio-3-phenylpropyl) amino] -123,4,6,7,8,12b-octahydro-6-oxo-pindo [2,1- a] [2] benzazepine-4-carboxylic acid and their pharmaceutically acceptable salts (European Patent Application No. 0 481 522 AL published on 22 April 1992, 209 ACS National Meeting, Division of Medical Chemistry, Abst. ) and application for a European patent

η Ν 657 453 A1 published on 14 June 1995) and its new intermediaries.

The present invention provides a novel process for the preparation of a compound of Formula L

in which G completes an aromatic ring selected from the group consisting of

wherein X is selected from the group consisting of S and NH; X2 is selected from the group consisting of S, O and NH; and the symbol R is selected from the group consisting of hydrogen, hydroxy, fendo

and C1 -C4 alkoxy; which comprises: (a) reacting a phthalimido aryl amino acid amide of general formula

O

wherein Ar is a radical selected from the group consisting of

wherein X is selected from the group consisting of S and NH; the symbol is selected from the group consisting of S.O and NH; and R 2 is selected from the group consisting of hydrogen, hydroxy, phenyl and C 1 -C 4 alkoxy; with glutaric dialdehyde to give a 1,4-dihydropyridine derivative of formula

or

in which Ar is as defined above; (b) reacting the 1,4-dihydropyridine derivative with an appropriate cyclizing agent to give 1,2,6,7,8,12b-hexahydro-6-oxopyrido [2,1-a] [2 ] -azepine of general formula

in which G has the meanings given above; (c) reacting 1,2,6,7,8,12b-hexahydro-6-oxopyrido [2,1-a] [2] azepine with carbon monoxide in the presence of an appropriate acid followed by hydration. The present invention provides a novel compound having the general formula:

O

in which Ar is a radical selected from the group consisting of

--R

W

Wherein X is selected from the group consisting of S and NH; X2 is selected from the group consisting of S, O and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl and C1 -C4 alkoxy.

In addition, the present invention provides a novel compound having the general formula:

G

In which G completes an aromatic ring selected from the group consisting of

X) is selected from the group consisting of S and NH; X2 is selected from the group consisting of S, O and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl and C1-6 alkoxy.

As used herein: a) the designation "-" refers to a link that protrudes out of the plane of the page; b) the designation "m ·· " ··" refers to a connection that protrudes behind the plane of the page; c) the designation "refers to a bond for which the stereochemistry is not designated; d) the term "C1 -C4 alkoxy" refers to a straight or branched chain alkoxy group containing 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy. n-butoxy, isobutoxy, t-butoxy. etc; e) the term "phenyl" refers to a radical of formula f) the designation

X 1 refers to a thienyl or pyrrolyl group and it is to be understood that the radical may be attached both in position 2 and in position 3; g) the designation

refers to an indolyl, benzothienyl or benzofuryl group and it is to be understood that the radical may be attached either in position 2 or in position 3, h) the designation

refers to a naphthyl group and it should be understood that the radical may

to be connected in both position 1 and position 2; It is to be understood that when G completes an aromatic ring

the compound of formula 1 has the formula

j) it is to be understood that when G completes the aromatic ring of general formula

the compound of general formula 1 has the general formula (k) it is to be understood that when G completes an aromatic ring of general formula

the compound of formula I has the general formula

1) it is to be understood that when G completes an aromatic ring of formula 10

the compound of formula I has the general formula

m) it is to be understood that when G completes an aromatic ring of general formula

the compound of formula I has the general formula

11 11

n) it is to be understood that when G completes an aromatic ring of formula

the compound of formula I has the formula

o) it is to be understood that when G completes an aromatic ring of formula

The compound of formula (I) has the formula

p) the expression "pharmaceutically acceptable salts" refers to both acid addition salts and base addition salts. The term "pharmaceutically acceptable acid addition salts" is intended to be applied to any non-toxic organic or inorganic acid addition salt of enkephalinase inhibitors and angiotensin converting enzyme, including [4S - [4 ', 7a (R *), 12β]]] - 7 - [(β-β-2 (S) -thio-3-phenylpropyl) amino] -1,2,3,4,6,7- (2R) -1,2b-octahydro-6-oxo-pyrido [2,1- a] [2] -benzazepine-4-carboxylic acid and [4S- [4Î ±, 7Î ± (R *), 12bβ]] - 7 - [( 1-oxo-2 (S) -acetylthio-3-phenylpropyl) amino] -1,2,3,4,6,7,8,12b-octahydro-6-oxo-pindo [Zi-a] [2] benzazepine- -4-carboxylic acid or any of its intermediates. Illustrative inorganic acids which form suitable salts are hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid salts of metals such as sodium monohydrogen orthophosphate and hydrogen and potassium sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartanic, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic. salicylic acid, 2-phenoxybenzoic acid and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such acids may exist both in hydrated form and in substantially anhydrous form. The term "pharmaceutically acceptable basic addition salts" is intended to be applied to any non-toxic organic or inorganic base addition salt of enkephalinase inhibitors and angiotensin converting enzyme, including [4S- [ 4a, 7a (R *), 12bβ]] - 7 - [(1-oxo-2 (S) -thio-3-phenyl-propylamino] -1,2,3,4,6,7,8,12b- dihydro-6-oxo-pyrido [2,1-a] [2] benzazepine-4-carboxylic acid or [4S- [4Î ±, 7Î ± (R *), 12β]] - 7 - [(1-oxo- 3-phenyl-propyl) -amino] -1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido [2, a] [2] benzazepine-4- carboxylic acid or any of its intermediates Illustrative bases which form suitable salts include alkali metal or alkaline earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia and aliphatic, cyclic or aromatic organic amines such as methylamine , dimethylamine, trimethylamine, triethylamine, diethylamine, isopropyldiethylamine, pyridine and picoline.

As will be appreciated by one skilled in the art, the methodology described herein may be used to prepare all of the 14

isomers in the 4-position and 7-position of the present intermediates, including 7 - [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)] - 1,2,3,4 , 6,7,8,12b-octahydro-6-oxopyrido [2,1-a] [2] benzazepine-4-carboxylic acid and thus the isomers of the enkephalinase inhibitors and the angiotensin converting enzyme produced therefrom. The stereochemistry at the 7-position of the intermediates is determined by the stereochemistry of the phthalimido aryl amino acid amide or the activated phthalimido aryl amino acid derivative selected. Specific 4-position isomers can be deployed and isolated using techniques known in the art, such as silica gel chromatography or on a chiral stationary phase or fractional recrystallization of the 4-position carboxylic acids or derivatives thereof as described herein descriptive memory; in European Patent Application No. 0 481 522 A1, published April 22, 1992; Siereochemistrv of Oraame Comoounds. E.L. Eliel and S.H.VVilen, VViley (1994); and in Enantiomers, Racemates. and Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981).

A general synthetic technique is shown in Scheme A. In Scheme A, all substituents, unless otherwise indicated, are as defined above. The starting compounds, reagents, techniques and processes used in Scheme A are well known and appreciated by one skilled in the art.

SCHEME A

-Air

phase b cyclization 16 SCHEME A Continued phase b cyclization

In Scheme A, an appropriate phthalimido aryl amino acid derivative of structure (1) is contacted with ammonia to provide a phthalimido aryl amino acid amide of structure (2) as is well known in the art.

In Scheme A, step a, an appropriate amide of the phthalimido aryl amino acid of structure (2) is contacted with glutaric dialdehyde to give the 1,4-dihydropyridine derivative of structure (3) .

A suitable derivative of the phthalimido aryl amino acid amide of structure (2) is readily available or is readily derived from aromatic amino acids which are well known in the art. Examples of aromatic amino acids which are useful in the present process include: phenylalanine, tryptophan, tyrosine and its ether, thien-2-ylalanine, 3-thienylanine, fur-2-ylalanine derivatives. fur-3-yalanine, benzothien-2-ylamine. indol-2-ylalanine, etc., The Peptides. vol. 5, E. Gross and J. Meienhoffer ed. (Academic Press, 1983). In addition, aromatic amino acids can be obtained by methods known in the art or analogously known in the art, such as D.A. Evans et al., J. Am. Chem. Soc., 112, 4011-4030 (1990); S. Ikegami et al, Tetrahedron 44, 5333-5342 (1988); W. Oppolzer et al., Tet. Lets. 30, 6009-6010 (1989), Svnthesis of Opticallv Active α-Amino Acids. R. M. Williams (Pergamon Press, Oxford 1989); M. J. O'Donnell ed .; q-Amino Acid Svnthesis. Tetrahedron Symposia in press, No. 33, Tetrahedron 44. N ° 17 (1988); U. Schollkopf, Pure Appl. Chem., 55, 1799 (1983); U. Hengartner et al., J. Org. Chem., 44, 3748-3752 (1979); M. J. CTDonnell et al., Tet. Lets., 2641-2644 (1978); M. J O'Donnell et al., Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al., J. Am. Chem. Soc. 110, 8520-8525 (1988).

Suitable amide of the phthalimido aryl amino acid of structure (2) is such that the stereochemistry is in accordance with the final product and Ar is as required to provide G as desired in the final product. It is to be understood that the glutaric dialdehyde can be generated in the reaction mixture from an appropriate equivalent glutaric dialdehyde. Suitable equivalents of glutaric dialdehyde include glutaric dialdehyde acetals. hydrated glutaric dialdehyde forms and the like. 18

For example, an appropriate amide of phthalimido aryl aminocarbonate of structure (2) with about 0.9 to 1.2 molar equivalents of glutaric dialdehyde is contacted. The reaction is carried out in a suitable solvent, such as dichloromethane. The reaction is carried out under acid catalysis conditions. Suitable catalysts are well known in the art and include p-toluenesulfonic acid. The reaction is carried out at a temperature in the range of from room temperature to the reflux temperature of the solvent. The reaction is carried out by removal of water by methods well known in the art, such as by azeotrope, by passing the reflux product over or through a drying agent, such as phosphorus pentoxide or by carrying out the reaction in the presence of an agent of suitable non-reactive drying, such as 3A molecular sieves, 4Å molecular sieves, MgS04 and the like. In general, the reaction requires between 2 hours and 4 days. The pellet can be isolated and purified using techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization.

In Scheme A, step b, an appropriate 1,4-dihydropyridine derivative of structure (3) is contacted with an appropriate cyclizing acid to give a 1,2,2,6,7,8,12b -hexahydro-6-oxopyrido [2, la] [2] azepine of structure (4).

For example, an appropriate 1,4-dihydropyridine derivative of structure (3) is contacted with an appropriate cyclizing acid. An appropriate cyclizing acid is such that it allows the formation of product without causing a significant degradation of both the starting compound and the product. Examples of suitable cyclizing acids include, sulfuric acid, trifluoromethane-19-sulfonic acid, sulfuric acid / trifluoroacetic anhydride mixtures and mixtures of trifluoromethanesulphonic acid / trifluoroacetic anhydride. The reaction is carried out alone in the appropriate cyclizing acid chosen or in a suitable aprotic solvent, such as dichloromethane. The reaction is carried out at temperatures between 10 ° C and 40 ° C. In general the reaction requires between 1 and 8 hours. The product may be isolated and purified using techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization.

In Scheme A, step c, an appropriate 1,2,6,7,8,12b-hexahydro-6-oxopyrido [2.1-a] [2] azepine of structure (4) is contacted with carbon in the presence of an appropriate acid followed by hydration to give a compound of formula I.

For example, an appropriate 1,2,6,7,8,12b-hexahydro-6-oxopyrido [2,1a] [2] azepine of structure (4) is contacted with an excess of carbon monoxide in the presence of an appropriate acid, such as sulfuric acid, followed by hydration. The reaction is carried out using the appropriate acid chosen as the solvent. The reaction may be carried out in a pressurized vessel to prevent leakage of the carbon monoxide. Carbon monoxide may be introduced as a gas or it may be generated in the reaction vessel or reactor by methods well known in the art, such as the decomposition of toric acid. The reaction is carried out at temperatures ranging from 0 to 100 ° C. The reaction may be carried out at pressures ranging from atmospheric pressure to 900 psi. When the reaction is carried out at a pressure which is higher than atmospheric pressure, it is necessary to use a suitable pressure reactor, such as closed or closed tubes, a pressure reactor or an autoclave. In general, the reaction requires between 1 and 48 hours. The addition of the carbon monoxide is followed by the hydration which is achieved by the addition of water. The product may be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization.

The following examples illustrate typical syntheses as described in Scheme A. These examples and preparations are to be understood as merely illustrative and not in any way limiting the scope of the invention. As used in the following examples and preparations, the following terms have the meanings indicated: "mg" refers to milligrams, "g" refers to grams, "kg" refers to kilograms, "mmol" refers to "mol" refers to moles, "μ" refers to microliters, "ml" refers to milliliters, "L" refers to liters, "° C" refers to degrees C "refers to the melting point," dec "refers to the decomposition," [a] D0 "refers to the specific rotation of sodium D-line at 20 ° C obtained in a cell of 1 "Me" refers to the concentration in g / 100 mL, "M" refers to molar, "2-PrOH" refers to isopropanol, "MeOH" refers to methanol, "Rt" , "TLC" refers to thin-layer chromatography, "psi" refers to pounds per square inch. PREPARATION 1 Synthesis of N-phthaloyl- (S) -phenylalanine acid chloride

Combine phthalic anhydride (1.82 kg, 12.3 mol), (S) -phenylalanine (1.84 kg, 11.1 mol) and anhydrous dimethylformamide (2.26 L). Stir at 21 115 - 120 ° C for 2 hours under a nitrogen atmosphere. Pour quickly into 32.6 L of stirred water and cool overnight at 0 ° C. filtered, washed with cold water (2 x 2 L) and dried in the air. Dissolve in a mixture of ethanol (8.05 L) and water (8.05 L) and heat to the reflux temperature. Filter by gravity, cool to room temperature and cool overnight at about 0 ° C. The crystallized product is filtered, washed with 9Â ethanol / water (2 x 2 L) at 50.degree. C. and air dried to give 2.96 kg (90.3%) of N-phthaloyl- (S ) -phenylalanine; Mp 177-179 ° C.

Combine N-phthaloyl- (S) -phenylalanine (50.2 g, 0.17 mol), methylene chloride (660 mL) and dimethylformamide (0.5 mL) under nitrogen. Oxalyl chloride (17.7 mL, 0.2 mol) is added over the course of about 5 minutes. Stir at room temperature for 3 hours and evaporate the solvent in vacuo to give the title compound. PREPARATION 2 Synthesis of phthalimido- (S) -phenylalanine amide

Combine N-phthaloyl- (S) -phenylalanine, acid chloride (100 nmol) and hexane (100 mL). 30 ml of a concentrated aqueous ammonia solution is added and stirred rapidly. After 10 minutes, the filtrate is washed with diethyl ether and water and dried in vacuo to give the title compound as a solid. EXAMPLE 1 (S) -N- [2- (13-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl] -1,4-dihydropyridine

Combine the phthalimido- (S) -phenylalanine amide (3.0 g, 10 mmol) and a solution of glutaric dialdehyde (2.0 g, 50% by weight in water) in dichloromethane (200 mL). Heat to reflux with azeotropic removal of the water from the refluxing product. P-Toluenesulfonic acid (60 mg) is added. Heating is continued at reflux. The reflux product is passed through dry 4Å molecular sieves in the oven. After 4 days, the reaction mixture is cooled to room temperature. Extract with 5% sodium bicarbonate solution. The 5% sodium bicarbonate solution is extracted with dichloromethane. The organic layers are combined and dried over Na2 SO4, filtered and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel eluting with 5% tetrahydrofuran / dichloromethane to give the title compound. EXAMPLE 11 (S) -N- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl] -1,4-dihydropyridine

Combine the phthalimido- (S) -phenylalanine amide (6.0 g, 20 mmol) and a solution of glutaric dialdehyde (4.0 mL, 50 wt.% In water) in dichloromethane (300 mL). Heat to reflux with azeotropic removal of the water from the refluxing product using a Dean-Stark trap. P-Toluenesulfonic acid (600 mg) is added. Heating to reflux with azeotropic removal of the water is continued. The Dean-Stark trap is replaced by a Soxhlet extractor charged with phosphorus pentoxide and heating is continued at reflux. After 24 hours, the reaction mixture is cooled to room temperature. Basic alumina is added to form a suspension. The suspension is filtered through a plug of silica gel and eluted with dichloromethane. Evaporate the filtrate in vacuo to give the title compound. EXAMPLE 2 (S) -7- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1,2,6,7,8,12b-hexahydro-6-oxo-pyrido [ air21 [benzazepine

A solution of (S) -N- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl] 4-dihydro-pyridine (1.1 g, 3.1 mmol) in dichloromethane (2 mL) was added trifluoromethanesulfonic acid (1.2 mL). After 2.5 hours, trifluoromethane-sultonic acid (1.2 mL) is added. After 4 hours. The reaction mixture is partitioned between ethyl acetate and 5% sodium bicarbonate solution. The organic layer is dried over Na2SO4, filtered and evaporated in vacuo to give a residue. The residue is chromatographed on silica gel eluting sequentially with 10% ethyl acetate / hexane and then with 25% ethyl acetate / hexane to give the title compound. EXAMPLE 2.1 (S) -7- [n-3-Dihydro-1,3-dioxo-2H-isomidol-2-yl) -1,2,6,7,8,12b-hexahydro-6-oxo-pyrido [ ~ 2] rbenzazepine

Combine sulfuric acid (3.0 mL, 96%) and 300 mL of trifluoroacetic anhydride. (S) -N- [2- (L3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl] -1,4-di (1.0 mmol). After 30 minutes, the reaction mixture is poured into a mixture of saturated aqueous sodium bicarbonate and ice. Extract with ethyl acetate and then with methylene chloride. The organic layers are combined and filtered through a plug of silica gel. The silica gel is washed with dichloromethane. Evaporate the filtrate in vacuo to give a residue. The residue is chromatographed on silica gel eluting sequentially with 10% ethyl acetate / hexane and then with 25% ethyl acetate / hexane to give the title compound. EXAMPLE 3 (S) -R- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-aza2benzazepine- 4-carboxylic acid ethyl ester 25

Combine (S) -7 - [(1,2-dihydro-1,3-dioxo-2H-isoindol-2-yl)] - 1,2,6,7,8,12b- dihydro-6-oxopyrido [2,1-a] [2] benzazepine (32 mg, 0.09 mmol) and sulfuric acid (1.0 mL, 95-98%) in a pressure vessel. 96% formic acid (200æl) is added and the vessel is rapidly closed. After 18 hours 10 mL of water is added. Extract the reaction mixture with ethyl acetate. Extract the organic layer with a saturated aqueous solution of potassium carbonate (5 x 10 mL). The aqueous layers are combined and acidified carefully with a 12M aqueous hydrochloric acid solution. Extract with chloroform (5 x 15 mL). The organic layers are combined, dried over MgSO4, filtered and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel eluting with 2/1 ethyl acetate / hexane containing 0.5% acetic acid to give the title compound. Rt = 0.14 (silica gel, 2/1 ethyl acetate / hexane containing 0.5% acetic acid). (S) -7- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a2benzazepine- 4-carboxylic acid

Combine (S) -7 - [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)] - 12,6,7,8,12b-hexahydro-6-oxopyrido [2 , 1α] [2] benzazepine (67 mg, 0.19 mmol) and sulfuric acid (2.0 mL, 95-98%) in a pressure vessel. 96% formic acid (400 μl) is added and the vessel is rapidly closed. After 18 hours the vessel is carefully opened and 5 ml of ice cold eagle is added. The reaction mixture is extracted repeatedly with chloroform. The organic layers are combined, dried over MgSO4, filtered and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel eluting with 2: 1 / 0.01 ethyl acetate / hexane / acetic acid to give the title compound. EXAMPLE 3.2

(S) -7- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)] - 1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido [2,1-a] [2] benzazepine- 4-carboxylic acid

Combine (S) -7 - [(1,2-dihydro-1,3-dioxo-2H-isoindol-2-yl)] - 1,2,6,7,8,12b- het. 6a-hydroxy-6-oxopyrido [2,1-a] [2] benzazepine (32 mg, 0.09 mmol) and sulfuric acid (1.0 mL, 95-98%) in a pressure vessel. Carbon monoxide (gas) is added by spraying at a pressure of 45 psi. After 18 hours, 10 mL of water is added. Extract the reaction mixture with ethyl acetate. Extract the organic layer with a saturated aqueous solution of potassium carbonate (5 x 10 mL). The aqueous layers are combined and acidified carefully with a 12M aqueous hydrochloric acid solution. Extract with chloroform (5 x 15 mL). The organic layers are combined, dried over MgSO4, filtered and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel to give the title compound. EXAMPLE 3.3 (S) -R-1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2.1 -α-21-benzazepine-4-carboxylic acid

Combine (S) -7 - [(1,2-dihydro-1,3-dioxo-2H-isoindol-2-yl)] - 1,2,6,7,7,12b-hexahydro-6 -oxopyrido [2,1-a] [2] benzazepine (800 mg, 2.2 mmol) and sulfuric acid (24 mL) in a pressure vessel. Carefully add formic acid (4.0 mL, 87 mmol) to minimize mixing and thus the formation of carbon monoxide. The pressure vessel is closed and carbon monoxide is added at 300 psi prior to stirring. (Caution, an abrupt increase in pressure occurs by mixing). After 16 hours the vessel is vented and the reaction mixture is added to 160 mL of an ice / water mixture. Extract is withdrawn with ethyl acetate. The organic layers are combined and extracted repeatedly with a 10% aqueous solution of potassium bicarbonate. The layers of the potassium bicarbonate solution are combined and cooled with an ice bath. Acidify to pH 1 using a 6M aqueous hydrochloric acid solution. The acidified aqueous layer is extracted repeatedly with ethyl acetate. The organic layers are combined and extracted with a saturated aqueous solution of sodium chloride, dried over MgSO4, filtered and evaporated in vacuo to give the title compound. PREPARATION 3

Preparation of [4S- (4α, 7α (R *). 12bB] -7-IO-oxo-2 (S) -acetylthio-3-phenyl-propylamino-1,2,3,6,7,8,12b-octahydro-6-oxo-pyridor2. 1-benzazepine-4-carboxylic acid. Synthesis of 4S-f4q. 7q (R * K 12bB)] - 7- (amino) -1,2,3,4,6,7,8,12b-octahydro-6-oxopyridote 1-a1b21benzazepine-4-carboxylic acid

Combine [4S- [4Î ±, 7Î ± (R *), 12bβ]] - 7 - [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)] - , 2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido [2,1-a] [2] benzazepine-4-carboxylic acid (1.63 kg, 4.03 mol ), triethylamine (429 mg, 4.24 mol) and methanol (5.59 kg). Add hydrazine monohydrate (241 g, 4.82 mol). Heat to reflux. After 3 hours, cool to 60 ° C and pour the reaction mixture into a mixture of water (7.326 kg) and 821 g of a 37% aqueous solution of hydrochloric acid. Evaporate in vacuo at 50 ° C until the reaction mixture is reduced to about 7.8 kg. The reaction mixture is diluted with water (8.078 kg) and the pH adjusted to about 2.82 using 37% aqueous hydrochloric acid solution. Heat to 50 ° C. After 1 hour, filter to remove the solids and wash with water (pH adjusted to 2.5 cm hydrochloric acid, 1.502 kg). The filtrate is combined and washed. The pH was adjusted to 7.22 using triethylamine. Evaporate in vacuo at 60 ° C until the reaction mixture is reduced to about 4.65 kg to give a suspension. The suspension is cooled with isopropanol (3.53 kg) and stirred for 30 minutes. Cool to 5 ° C to give a solid. The solid is collected by filtration, washed with isopropanol and dried to give the title compound (933 g, 84.4%). Synthesis of [4S- [4α. 7a (R *). (R) -bromo-3-phenylpropyl) -aminol-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-aza-2benzazepine-4-carboxylic acid methyl ester Mixture- 3-phenyl-2 (R) -bromopropionic acid (967 g, 4.22 mol), tetrahydrofuran (7.74 kg) and N-hydroxysuccinimide (607 g, 5.27 mol) was cooled and cooled to 5 ° C. A solution of 1,3-dicyclohexylcarbodiimide (828 g, 4.01 mol) in tetrahydrofuran (1.936 kg) is slowly added over a period of 2 ½ hours, maintaining the temperature in the range from -3 and 3 ° C. Stir for 19 hours, 2,3-dicyclohexylurea is removed by vacuum filtration and the filter cake is washed with tetrahydrofuran (1.927 kg). The filtrate and the washing liquid are placed in a 50 liter round bottom flask with a drain in the bottom, [4S- [4α, 7α (R *), 12bβ]] - 7- (amino) -1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido [2,1-a] [2] benzazepine-4-carboxylic acid (869 g, 3.17 mol) and is stirred at 22 ° C for 5.5 hours. Triethylamine (77 g, 0.76 mol) is added and stirred for an additional 17 hours at 22 ° C. Dilute with ethyl acetate (10.427 kg), wash with water (9.94 kg) with 37% hydrochloric acid (214.2 g) and sodium chloride (418 g), then with 12.328 kg of water with 418 g of sodium chloride. Dry (MgSO4), filter, and wash the filter cake with ethyl acetate (2.193 kg). The solvent is evaporated in vacuo, isopropanol (4.210 kg) is added, stirred at a temperature of 12-16 ° C for 17 hours, cooled and the product is isolated by vacuum filtration. Wash with isopropanol (621 g) and dry to give the title compound (940 g, 61%). Synthesis of [4S- [4Î ±, 7Î ± (R *), 12bβ]] - 7- (1-Oxo-2 (S) -acetylthio-3-phenylpropyl) amino] -1,2,3,4,6,7,8,12b-octahydro- [4S- [4Î ±, 7Î ± (R *), 12bβ]] - 7 - [(1-oxo-2 (R) -bromo-3-phenylpropyl) -piperazin- amino] -1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido [2,1-a] [2] benzazepine-4-carboxylic acid (1.052 kg, 2.17 mol), acetone ( (207.1 g, 2.72 mol), cooled to -2 ° C and a solution of potassium hydroxide (279.5 g) in water (270 ml) was added dropwise over 10 minutes. g) Stir at -4 ° C for 23 hours, add 1.054 kg of water containing 210 g of 37% hydrochloric acid and evaporate the solvent in vacuo. toluene (11,517 kg) at 43øC, transferred to a 22 liter round bottom flask with a drain at the bottom and washed with 4.067 kg of water. The temperature was heated at 41øC with 4.099 kg of water containing 213 g of sodium chloride. the solvent is evaporated in vacuo, the solid residue is dissolved in toluene (10.239 kg), filtered and cooled. After cooling to -2 ° C, the solid was collected by vacuum filtration, washed with toluene (1.103 kg) and dried under vacuum at 80 ° C to give the title compound (859 g, 82.5% %).

Preparation of (4S, 4R) -4- 7a ('R *). 12bBn-7- (1-oxo-2 (S) -thio-3-phenylpropyl) aminol-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,2-ab2benzazepine-4-carboxylic acid

[4S- [4Î ±, 7Î ± (R *), 12bβ]] - 7 - [(1-oxo-2 (S) -acetylthio-3-phenylpropyl) amino] -1,2,3,4,6,7 4-carboxylic acid (57 mg, 0.12 mmol) in deoxygenated methanol (3 ml) containing lithium hydroxide , 25 mL, 1M in water, 0.25 mmol). Stir for 30 minutes under argon at room temperature. The volume is reduced to 1.5 mL in vacuo, and then added dropwise to a rapidly stirred solution of 2 mL of 2M hydrochloric acid. The resulting precipitate is collected, washed with water and dried in a desiccator under vacuum for 1 hour. Dry at 5 ° C overnight to give the title compound as an electrostatic white powder.

Lisbon, March 17, 2000 Ο Αηρ * ηϊρ · ifir-irs! nr ·. DrnrvIa-tnHii nHijgfpQj

125 «LISBON

Claims (9)

A process for the preparation of a compound of general formula in which G completes an aralkaric ring selected from the group consisting of wherein X] is selected from the group consisting of S and NH; X2 is selected from the group consisting of S, O and NH; and R is selected from the group consisting of hydrogen, hydroxy. phenyl and C 1 -C 4 alkoxy: which comprises: (a) reacting an amide of the phthalimido aryl amino acid of formula O in which Ar is a radical selected from the group consisting of wherein X | is selected from the group consisting of S and NH; X2 is selected from the group consisting of S, O and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl and C1 -C4 alkoxy; with glutaric dialdehyde to give a 1,4-dihydropyridine derivative of general formula 3 in which Ar is as defined above; (b) reacting the 1,4-dihydropyridine derivative with an appropriate cyclizing agent to give 1,2,6,7,8,12b-hexahydro-6-oxopyrido [2, l] [ 2] -azepine of general formula in which G is as defined above; (c) reacting 1,2,6,7,8,12b-hexahydro-6-oxopyrido [2,1-a] [2] azepine with carbon monoxide in the presence of an appropriate acid followed by hydration. A process according to claim 1 wherein the appropriate cyclizing acid is a mixture of trifluoromethanesulfonic acid / trifluoroacetic anhydride. A process according to claim 1 wherein the appropriate cyclizing acid is a mixture of sulfuric acid / trifluoroacetic anhydride. A compound of the general formula in which Ar is a radical selected from the group consisting of wherein X1 is selected from the group consisting of S and NH; X2 is selected from the group consisting of S.O and NH, and R3 is selected from the group consisting of hydrogen, hydroxy, phenyl and C1 -C4 alkoxy. A compound according to claim 4 which is (S) -N- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo- 3-phenylpropyl] -1,4-dihydro-pyridine. A compound according to claim 4 which is (R) -N- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo- 3-phenylpropyl] -1,4-dihydro-pyridine. A compound of general formula 5 in which G completes an aromatic ring selected from the group consisting of wherein X1 is selected from the group consisting of S and NH; X2 is selected from the group consisting of S, O and NH; and R 2 is selected from the group consisting of hydrogen, hydroxy, phenyl and C 1 -C 4 alkoxy. A compound according to claim 7 which is (S) -7 - [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1,2,6,7- 7,8,12b-hexahydro-6-oxopyrido [2,1-a] [2] -6-benzazepine. A compound according to claim 7 which is (S) -7 - [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) 7,8,12b-hexahydro-6-oxopyrido [2,1-a] [2] benzazepine. Lisbon, March 17, 2000 The present invention relates to novel processes for the preparation of intermediates of general formula (I) and to their novel intermediates. The present invention relates to novel processes for the preparation of intermediates of general formula (I) and their novel intermediates intermediates which are useful in the preparation of enkephalinase and angiotensin converting enzyme inhibitors. Lisbon,